No agent has been developed to inhibit nerve cell death in neurodegenerative diseases such as Alzeheimer's disease and Parkinson's disease and prevent these diseases from progressing.
Alzeheimer's disease is characterized by senile plaque formation and neurofibrillary degeneration along with neuronal degeneration and dropout. Senile plaques, the most characteristic pathological feature in the Alzeheimer's diseased brain, are produced by extracellular deposition of β-amyloid protein (hereinafter also abbreviated as Aβ), which is a metabolite of β-amyloid precursor protein (hereinafter also abbreviated as βAPP) (Biochem. Biophys. Res. Commun. 122, 1131 (1984); Proc. Natl. Acad. Sci. USA. 82, 4245 (1985); J. Neurochem. 46, 1820 (1986); Neuron 6, 487 (1991)). Aβ comprising 40 or 42 amino acids is known to be toxic to nerve cells (Science 250, 279 (1990); Brain Res. 563, 311 (1991); J. Neurosci. 12, 376 (1992)) and also known to induce neurofibrillary degeneration (Proc. Natl. Acad. Sci. USA. 90, 7789-7793 (1993)).
βAPP is not only metabolized to Aβ, but also metabolized in such a way as not to produce Aβ; the resulting-metabolite, soluble β-amyloid precursor protein (soluble APP, also abbreviated as sAPP), is secreted into the extracellular environment (Science 248, 492 (1990); Science 248, 1122 (1990)). There are many reports that this sAPP operate as a neurotrophic factor, i.e. stimulating the elongation of the nerve cells and inhibiting the nerve cell death by using primary cultured nerve cells or neuroblastoma PC12 cells and so on (Neuron 9, 129 (1992); Neuron 10, 243 (1993); Physiol. Rev. 77, 1081 (1997)). It is also reported that the sAPP level is reduced in the cerebral fluid of patients with Alzeheimer's disease (Lancet 340, 453 (1992); Ann. Neurol. 32, 215 (1992); Proc. Natl. Acad. Sci. USA 89, 2551 (1992); Alzheimer Disease and Associated Disorders 11, 201 (1997)). This suggests that in Alzeheimer's disease, βAPP metabolism is more likely to shift to the production of Aβ rather than sAPP, i.e., an increase and extracellular accumulation of cytotoxic Aβ, or a decrease of neurotrophic factor sAPP may play a very critical role in the onset of the disease. Thus, compounds capable of stimulating sAPP production and secretion in nerve system tissues are expected as prophylactic and/or therapeutic agents for various neurodegenerative diseases because of their ability to reduce nerve cell damage caused by various factors and/or prevent nerve cell death, with the aid of the neurotrophic action of sAPP. At the same time, such compounds also have the ability to inhibit the production of cytotoxic Aβ and are particularly expected as prophylactic and/or therapeutic agents for Alzeheimer's disease (J. Biol. Chem. 268, 22959 (1993); Ann. New York Acad. Sci. 777, 175 (1997)).
In fact, phorbol ester, which is an activator of protein kinase C (hereinafter also abbreviated as PKC), is known not only to strongly stimulate sAPP secretion, but also to inhibit the production and secretion of Aβ (Proc. Natl. Acad. Sci. USA. 87, 6003 (1990); Proc. Natl. Acad. Sci. USA. 90, 9195 (1993); J. Neurochem. 61, 2326 (1993); J. Biol. Chem. 269, 8376 (1994)).
Therefore, it has been made attempts to increase the level of sAPP by using various types of cells and brain tissue sections. For example, in addition to phorbol ester mentioned above, other compounds are also reported to stimulate sAPP secretion, including M1 muscarinic receptor agonists (Science 258, 304 (1992); Proc. Natl. Acad. Sci. USA. 89, 10075 (1992); J. Neurosci. 15, 7442 (1995)), glutamate agonists (Proc. Natl. Acad. Sci. USA. 92, 8083 (1995)) and serotonin agonists (J. Biol. Chem. 23, 4188 (1996)), it is believed since these agonists activate PKC, tyrosine kinase or phospholipase A2 through their respective receptors.